Modelling negative feedback networks for activating transcription factor 3 predicts a dominant role for miRNAs in immediate early gene regulation

Activating transcription factor 3 (Atf3) is rapidly and transiently upregulated in numerous systems, and is associated with various disease states. Atf3 is required for negative feedback regulation of other genes, but is itself subject to negative feedback regulation possibly by autorepression. In cardiomyocytes, Atf3 and Egr1 mRNAs are upregulated via ERK1/2 signalling and Atf3 suppresses Egr1 expression. We previously developed a mathematical model for the Atf3-Egr1 system. Here, we adjusted and extended the model to explore mechanisms of Atf3 feedback regulation. Introduction of an autorepressive loop for Atf3 tuned down its expression and inhibition of Egr1 was lost, demonstrating that negative feedback regulation of Atf3 by Atf3 itself is implausible in this context. Experimentally, signals downstream from ERK1/2 suppress Atf3 expression. Mathematical modelling indicated that this cannot occur by phosphorylation of pre-existing inhibitory transcriptional regulators because the time delay is too short. De novo synthesis of an inhibitory transcription factor (ITF) with a high affinity for the Atf3 promoter could suppress Atf3 expression, but (as with the Atf3 autorepression loop) inhibition of Egr1 was lost. Developing the model to include newly-synthesised miRNAs very efficiently terminated Atf3 protein expression and, with a 4-fold increase in the rate of degradation of mRNA from the mRNA/miRNA complex, profiles for Atf3 mRNA, Atf3 protein and Egr1 mRNA approximated to the experimental data. Combining the ITF model with that of the miRNA did not improve the profiles suggesting that miRNAs are likely to play a dominant role in switching off Atf3 expression post-induction.

Any response? How demand response could be enhanced based on early UK experience

Policy makers are in broad agreement that demand response should play a major role in EU electricity systems and provide much needed future system flexibility. Yet, little demand response has been forthcoming in member states to date. This paper identifies some of the technical potential for demand response, based on empirical data from one UK demand aggregator. Half-hourly electricity readings of demand during normal operation and during response events have been analysed for different industry and service sectors. We review these findings in the context of ongoing EU policy developments with particular focus on the role appropriate arrangements to enhance the available resource. We conclude that in some sectors appropriate policy and regulation could triple the available response capacity and thereby lead to stronger commercial uptake of demand response.

Holocene variations in peatland methane cycling associated with the Asian summer monsoon system

Atmospheric methane concentrations decreased during the early to middle Holocene; however, the governing mechanisms remain controversial. Although it has been suggested that the mid-Holocene minimum methane emissions are associated with hydrological change, direct evidence is lacking. Here we report a new independent approach, linking hydrological change in peat sediments from the Tibetan Plateau to changes in archaeal diether concentrations and diploptene delta C-13 values as tracers for methanogenesis and methanotrophy, respectively. A minimum in inferred methanogenesis occurred during the mid-Holocene, which, locally, corresponds with the driest conditions of the Holocene, reflecting a minimum in Asian monsoon precipitation. The close coupling between precipitation and methanogenesis is validated by climate simulations, which also suggest a regionally widespread impact. Importantly, the minimum in methanogenesis is associated with a maximum in methanotrophy. Therefore, methane emissions in the Tibetan Plateau region were apparently lower during the mid-Holocene and partially controlled by interactions of large-scale atmospheric circulation.

Validation of the NANA (Novel Assessment of Nutrition and Ageing) touch screen system for use at home by older adults

Prospective measurement of nutrition, cognition, and physical activity in later life would facilitate early detection of detrimental change and early intervention but is hard to achieve in community settings. Technology can simplify the task and facilitate daily data collection. The Novel Assessment of Nutrition and Ageing (NANA) toolkit was developed to provide a holistic picture of an individual's function including diet, cognition and activity levels. This study aimed to validate the NANA toolkit for data collection in the community. Forty participants aged 65 years and over trialled the NANA toolkit in their homes for three 7-day periods at four-week intervals. Data collected using the NANA toolkit were compared with standard measures of diet (four-day food diary), cognitive ability (processing speed) and physical activity (self-report). Bland–Altman analysis of dietary intake (energy, carbohydrates, protein fat) found a good relationship with the food diary and cognitive processing speed and physical activity (hours) were significantly correlated with their standard counterparts. The NANA toolkit enables daily reporting of data that would otherwise be collected sporadically while reducing demands on participants; older adults can complete the daily reporting at home without a researcher being present; and it enables prospective investigation of several domains at once

Improving the health forecasting alert system for cold weather and heat-waves in England: a proof-of-concept using temperature-mortality relationships

Objectives In this study a prototype of a new health forecasting alert system is developed, which is aligned to the approach used in the Met Office’s (MO) National Severe Weather Warning Service (NSWWS). This is in order to improve information available to responders in the health and social care system by linking temperatures more directly to risks of mortality, and developing a system more coherent with other weather alerts. The prototype is compared to the current system in the Cold Weather and Heatwave plans via a case-study approach to verify its potential advantages and shortcomings. Method The prototype health forecasting alert system introduces an “impact vs likelihood matrix” for the health impacts of hot and cold temperatures which is similar to those used operationally for other weather hazards as part of the NSWWS. The impact axis of this matrix is based on existing epidemiological evidence, which shows an increasing relative risk of death at extremes of outdoor temperature beyond a threshold which can be identified epidemiologically. The likelihood axis is based on a probability measure associated with the temperature forecast. The new method is tested for two case studies (one during summer 2013, one during winter 2013), and compared to the performance of the current alert system. Conclusions The prototype shows some clear improvements over the current alert system. It allows for a much greater degree of flexibility, provides more detailed regional information about the health risks associated with periods of extreme temperatures, and is more coherent with other weather alerts which may make it easier for front line responders to use. It will require validation and engagement with stakeholders before it can be considered for use.

Mapping Educational Specialist knowHow (MESH): the building of a knowledge management system for research informed practice

In this invited article the authors present an evaluative report on the development of the MESHGuides project (http://www.meshguides.org/). MESHGuides’ objective is to provide education with an international knowledge management system. MESHGuides were conceived as research summaries for supporting teachers’ in developing evidence-based practice. Their aim is to enhance teachers’ capacity to engage actively with research in their own classrooms. The original thinking for MESH arose from the work of UK-based academics Professor Marilyn Leask and Dr Sarah Younie in response to a desire, which has recently gathered momentum in the UK, for the development of a more research-informed teaching profession and for the establishment of an on-line platform to support evidence-based practice (DfE, 2015; Leask and Younie 2001; OECD 2009). The focus of this article is on how the MESHGuides project was conceived and structured, the technical systems supporting it and the practical reality for academics and teachers of composing and using MESHGuides. The project and the guides are in the early stages of development, and discussion indicates future possibilities for more global engagement with this knowledge management system.

Early membrane estrogenic effects required for full expression of slower genomic actions in a nerve cell line.

Interpretations of steroid hormone actions as slow, nuclear, transcriptional events have frequently been seen as competing against inferences of rapid membrane actions. We have discovered conditions where membrane-limited effects potentiate later transcriptional actions in a nerve cell line. Making use of a two-pulse hormonal schedule in a transfection system, early and brief administration of conjugated, membrane-limited estradiol was necessary but not sufficient for full transcriptional potency of the second estrogen pulse. Efficacy of the first pulse depended on intact signal transduction pathways. Surprisingly, the actions of both pulses were blocked by a classical estrogen receptor (ER) antagonist. Thus, two different modes of steroid hormone action can synergize.

A Romano-British settlement with ovens and field system at Theobalds Road, Wivelsfield, East Sussex

Excavation west of Wivelsfield, East Sussex, revealed part of an early Romano-British settlement. One of the round-houses may have had a non-domestic, possibly ritual, function. The settlement appears to have been subsequently incorporated within a rectilinear arrangement of field/enclosure ditches. Along the edge of one of these ditches were built a series of features interpreted as ovens, of varying form and likely use, from which charred waste from cereal processing and charcoal from coppiced woodland were recovered.

Comparison of biological behavior between early-stage adenocarcinoma and squamous cell carcinoma of the uterine cervix

Objectives: (1) To compare the anatomopathological variables and recurrence rates in patients with early-stage adenocarcinoma (AC) and squamous cell carcinoma (SCC) of the uterine cervix; (2) to identify the independent risk factors for recurrence. Study design: This historical cohort study assessed 238 patients with carcinoma of the uterine cervix (113 and IIA), who underwent radical hysterectomy with pelvic lymph node dissection between 1980 and 1999. Comparison of category variables between the two histological types was carried out using the Pearson`s X-2 test or Fisher exact test. Disease-free survival rates for AC and SCC were calculated using the Kaplan-Meier method and the curves were compared using the log-rank test. The Cox proportional hazards model was used to identify the independent risk factors for recurrence. Results: There were 35 cases of AC (14.7%) and 203 of SCC (85.3%). AC presented lower histological grade than did SCC (grade 1: 68.6% versus 9.4%; p < 0.001), lower rate of lymphovascular space involvement (25.7% versus 53.7%; p = 0.002), lower rate of invasion into the middle or deep thirds of the uterine cervix (40.0% versus 80.8%; p < 0.001) and lower rate of lymph node metastasis (2.9% versus 16.3%; p = 0.036). Although the recurrence rate was lower for AC than for SCC (11.4% versus 15.8%), this difference was not statistically significant (p = 0.509). Multivariate analysis identified three independent risk factors for recurrence: presence of metastases in the pelvic lymph nodes, invasion of the deep third of the uterine cervix and absence of or slight inflammatory reaction in the cervix. When these variables were adjusted for the histological type and radiotherapy status, they remained in the model as independent risk factors. Conclusion: The AC group showed less aggressive histological behavior than did the SCC group, but no difference in the disease-free survival rates was noted. (C) 2006 Elsevier Ireland Ltd. All rights reserved.

New molecular variants of hypothalamus-pituitary-gonad axis genes and their association with early puberty phenotype in Bos taurus indicus (Nellore)

Endocrine system plays a major role in the control of reproductive functions which are regulated by the hypothalamus-pituitary-gonad axis and its interactions. FSH and LH receptor genes are expressed at the gonads and GnRH receptor gene is expressed at the anterior pituitary gland. Misense mutations of the FSH, LH or GnRH receptors, activating or inactivating their functions in mammals, are potentially useful to allow the understanding of the role of this group of gonadotropins in reproductive phenotypes as early puberty and birth interval length. In the present study, polymorphisms in bovine exon 11 and 3`UTR of LHR, exon 10 and 3`UTR of FSHR and GnRHR genes were characterized with some of them resulting in changes in the aminoacidic chain. These polymorphic sites were found in a Bos taurus indicus (Nellore) female population by means of PCR-SSCP and DNA sequencing. Association between nucleotidic/aminoacidic changes and early puberty were determined by Chi-square analysis. It was found association between FSHR 3`UTR polymorphisms at position 2181, 2248 and 2249 bp and early puberty phenotype (p < 0.05). The presence of these new molecular markers might be considered in further studies to validate its correlation with early puberty or other reproduction associated phenotypes in cattle breeds. (C) 2007 Published by Elsevier B.V.

The South American Monsoon System and the 1970s climate transition

The South American Monsoon System (SAMS) is characterised by intense convective activity and precipitation during austral summer. This study investigates changes in the onset, demise and duration of SAMS during 1948-2008. The results show a significant change in these characteristics in the early 1970s. Onset becomes steadily earlier from 1948 to early 1970s and has occurred earlier than 23-27 October after 1972-1973. Demise dates have remained later than 21-25 April after the mid-to-late 1970s. SAMS duration shows a statistical changepoint in the summer of 1971-1972 such that the mean duration was similar to 170 days (1948-1972) and 195 days (1972-1982). Vertically integrated moisture flux is used to diagnose changes in mean state and reveal statistically significant increases over South America after 1971-1972. Copyright. (C) 2010 Royal Meteorological Society

Dissecting the brain`s fear system reveals the hypothalamus is critical for responding in subordinate conspecific intruders

Effective defense against natural threats in the environment is essential for the survival of individual animals. Thus, instinctive behavioral responses accompanied by fear have evolved to protect individuals from predators and from opponents of the same species (dominant conspecifics). While it has been suggested that all perceived environmental threats trigger the same set of innately determined defensive responses, we tested the alternate hypothesis that different stimuli may evoke differentiable behaviors supported by distinct neural circuitry. The results of behavioral, neuronal immediate early gene activation, lesion, and neuroanatomical experiments indicate that the hypothalamus is necessary for full expression of defensive behavioral responses in a subordinate conspecific, that lesions of the dorsal premammillary nucleus drastically reduce behavioral measures of fear in these animals, and that essentially separate hypothalamic circuitry supports defensive responses to a predator or a dominant conspecific. It is now clear that differentiable neural circuitry underlies defensive responses to fear conditioning associated with painful stimuli, predators, and dominant conspecifics and that the hypothalamus is an essential component of the circuitry for the latter two stimuli.

Early Increase in Autoantibodies Against Human Oxidized Low-Density Lipoprotein in Hypertensive Patients After Blood Pressure Control

BACKGROUND Oxidized lipoproteins and antioxidized low-density lipoprotein (anti-oxLDL) antibodies (Abs) have been detected in plasma in response to blood pressure (BP) elevation, suggesting the participation of the adaptive immune system. Therefore, treatment of hypertension may act on the immune response by decreasing oxidation stimuli. However, this issue has not been addressed. Thus, we have here analyzed anti-oxLDL Abs in untreated (naive) hypertensive patients shortly after initiation of anti hypertensive therapeutic regimens. METHODS Titers of anti-oxLDL Abs were measured in subjects with recently diagnosed hypertension on stage 1 (n = 94), in primary prevention of coronary disease, with no other risk factors, and naive of anti hypertensive medication at entry. Subjects were randomly assigned to receive perindopril, hydrochlorothiazide (HCTZ), or indapamide (INDA) for 12 weeks, with additional perindopril if necessary to achieve BP control. Abs against copper-oxidized LDL were measured by enzyme-linked immunosorbent assay. RESULTS Twelve-week antihypertensive treatment reduced both office-based and 24-h ambulatory BP measurements (P < 0.0005). The decrease in BP was accompanied by reduction in thiobarbituric acid-reactive substances (TBARS) (P < 0.05), increase in anti-oxLDL Ab titers (P < 0.005), and improvement in flow-mediated dilation (FMD) (P < 0.0005), independently of treatment. Although BP was reduced, we observed favorable changes in anti-oxLDL titers and FMD. CONCLUSIONS We observed that anti-oxLDL Ab titers increase after antihypertensive therapy in primary prevention when achieving BP targets. Our results are in agreement with the concept that propensity to oxidation is increased by essential hypertension and anti-oxLDL Abs may be protective and potential biomarkers for the follow-up of hypertension treatment.

Evolution of a rift basin dominated by subaerial deposits: The Guaritas Rift, Early Cambrian, Southern Brazil

Most existing models for the evolution of rift basins predict the development of deep-water depositional systems during the stage of greatest tectonic subsidence, when accommodation generation potentially outpaces sedimentation. Despite this, some rift basins do not present deep-water systems, instead being dominated by subaerial deposits. This paper focuses on one of these particular rift basins, the Cambrian Guaritas Rift, Southern Brazil, characterized by more than 1500 m of alluvial and aeolian strata deposited in a 50-km-wide basin. The deposits of the Guaritas Rift can be ascribed to four depositional systems: basin-border alluvial fans, bedload-dominated ephemeral rivers, mixed-load ephemeral rivers and aeolian dune fields. These four systems are in part coeval and in part succeed each other, forming three stages of basin evolution: (i) Rift Initiation to Early Rift Climax stage, (ii) Mid to Late Rift Climax stage, and (iii) Early Post-Rift stage. The first stage comprises most of the Guaritas Group and is characterized by homogeneous bed-load-dominated river deposits, which do not clearly record the evolution of subsidence rates. The onset of sedimentation of finer-grained deposits occurred as a consequence of a reactivation event that changed the outline of the basin and the distribution of the nearby highlands. This strongly suggests that the capture of the main river system to another depression decreased the sediment supply to the basin. The study of the Guaritas Rift indicates that rift basins in which the sediment supply exceeds the accommodation generation occur as a consequence of moderate subsidence combined with the capture of a major river system to the basin during the initial stages of basin evolution. In these basins, changes in the average discharge of the river system or tectonic modification of the drainage network may be the major control on the stratigraphic architecture. (c) 2009 Published by Elsevier B.V.

Using system dynamics for collaborative design : a case study

Background  In order to facilitate the collaborative design, system dynamics (SD) with a group modelling approach was used in the early stages of planning a new stroke unit. During six workshops a SD model was created in a multiprofessional group. Aim To explore to which extent and how the use of system dynamics contributed to the collaborative design process. Method A case study was conducted using several data sources. Results SD supported a collaborative design, by facilitating an explicit description of stroke care process, a dialogue and a joint understanding. The construction of the model obliged the group to conceptualise the stroke care and experimentation with the model gave the opportunity to reflect on care. Conclusion SD facilitated the collaborative design process and should be integrated in the early stages of the design process as a quality improvement tool.